Outcomes of Percutaneous Coronary Intervention Performed With or Without Preprocedural Dual Antiplatelet Therapy

Abstract

Background: Preprocedural dual antiplatelet therapy (DAPT) in percutaneous coronary interventions (PCI) has been shown to improve outcomes; however, the efficacy of the procedure and its complications in Japanese patients remain largely unexplored, so we examined the risks and benefits of DAPT before PCI and its association with in-hospital outcomes.

Methods and Results: We analyzed data from patients who had undergone PCI at 12 centers within the metropolitan Tokyo area between September 2008 and September 2013. Our study group comprised 6,528 patients, of whom 2,079 (31.8%) were not administered preprocedural DAPT. Non-use of preprocedural DAPT was associated with death, postprocedural shock, or heart failure (odds ratio [OR]: 1.47, 95% confidence interval [CI]: 1.10–1.96, P=0.009), and postprocedural myocardial infarction (OR: 1.41, 95% CI: 1.18–1.69, P<0.001) after adjusting propensity scores for known predictors of in-hospital complications. Non-use of DAPT was not associated with procedure-related bleeding complications (OR: 0.98, 95% CI: 0.71–1.59, P=0.764).

Conclusions: Approximately one-third of the patients who underwent PCI did not receive preprocedural DAPT despite guideline recommendations. Our results indicate that patients undergoing PCI with DAPT have a lower risk of postprocedural cardiac events without any increased bleeding risk. Further studies are needed to implement the use of DAPT in real-world PCI. (Circ J 2015; 79: 2598–2607)

Dual antiplatelet therapy (DAPT) improves outcomes in patients undergoing percutaneous coronary interventions (PCI), mainly owing to the therapy’s antiplatelet effects on different stages of the platelet activation process. Previous studies have shown that preprocedural DAPT significantly reduces major cardiovascular events in patients with ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and planned PCI cases, compared with patients receiving single antiplatelet therapy.^1–3 As a consequence, although there are slight differences in antiplatelet regimens in different guidelines, the guidelines of the American College of Cardiology, American Heart Association, European Society of Cardiology, and Japanese Circulation Society all recommend pre-PCI DAPT as class I.^4–10

Editorial p 2544

Although, the enhanced antithrombotic effects of DAPT should provide additional protection against thrombotic events for patients undergoing PCI, DAPT could also increase the risk of bleeding complications. Particularly, the safety of DAPT in an East Asian population vulnerable to bleeding is unknown.^11,12 The current guidelines from the Japanese Circulation Society are based solely on evidence from Western countries, and few trial results from studies focusing on East Asian populations are available. Furthermore, the actual bleeding complication rate in Japanese patients who undergo PCI has not yet been determined. Consequently, despite the Japanese guidelines, the use of preprocedural DAPT still varies among Japanese institutions; a single multicenter study from Japan showed that only 66.7% of Japanese patients who had undergone primary PCI for STEMI received preprocedural DAPT.¹³

To the best of our knowledge, no studies have specifically evaluated the risks and benefits of pre-PCI DAPT and the association with in-hospital outcomes in Japan. Therefore, we investigated the prevalence of DAPT use in a multicenter Japanese PCI registry-based study and evaluated the effect of DAPT on in-hospital outcomes, including PCI-related MI.

Methods

Study Design

The Japan Cardiovascular Database Keio interhospital Cardiology Study (JCD-KiCS) is a large, ongoing, prospective, multicenter registry that contains the clinical background and outcome data (approximately 200 variables) from consecutive PCI cases.^14–17 Participating hospitals were instructed to record data from consecutive hospital visits for patients undergoing PCI using any commercially available coronary device and to register the data in an internet database. The information was tracked by the site investigator and by the responsible coordinators. The database system was checked to ensure that the reported data were complete and internally consistent. The decision to perform PCI was made according to the investigators’ clinical assessment of the patient. The study did not mandate specific interventional or surgical techniques such as vascular access or use of specific stents or closure devices.

The majority of the clinical variables in the JCD were defined according to the National Cardiovascular Data Registry (NCDR). The NCDR is a large PCI registry system, sponsored by the American College of Cardiology, with more than 1,000,000 entries related to ischemic heart disease and more than 500,000 entries for PCI collected from more than 500 institutions in the USA.¹⁸ The variables were compared to determine the factors that lead to disparities in PCI management.

Patients who received aspirin and clopidogrel within 24 h before the procedure were defined as DAPT users. Patients with clinical contraindications for DAPT therapy were excluded from the current analysis. In this study, we focused on clopidogrel and excluded other antiplatelet combinations such as cilostazol or ticlopidine. In Japan, the approved loading dose of clopidogrel is 300 mg and therefore it was the only dose provided to the patients in this registry.¹⁹ Prasugrel and ticagrelor were not approved at the time of this analysis. In Japan, the recommended loading dose of aspirin is 162–325 mg.^7,8 Patients did not receive GP IIb/IIIa inhibitors, as they were not approved in Japan at the time of this study. In a randomized clinical trial, the efficacy of abciximab in preventing post-PCI coronary events in Japanese patients was not detected, and the incidence of bleeding complications tended to increase in a dose-dependent manner.²⁰ Postprocedural MI was defined as postprocedural creatine phosphokinase values greater than three times the upper limit. Cardiogenic shock was defined as a sustained (>30 min) episode of systolic blood pressure <90 mmHg, a cardiac index of <2.2 L·min^–1·m^–2 determined to be secondary to cardiac dysfunction, and/or the requirement for parenteral inotropic or vasopressor agents or mechanical support. Heart failure (HF) was defined as physician documentation or report of any of the following clinical symptoms of HF: unusual dyspnea or rales on light exertion, jugular venous distension, pulmonary edema on physical examination, or pulmonary edema evident on a chest radiograph presumably associated with cardiac dysfunction.

Information Disclosure

Before the launch of the JCD, information on the objectives of the present study, its social significance, and an abstract were provided to register this clinical trial with the University Hospital Medical Information Network. This Network is recognized by the International Committee of Medical Journal Editors as an acceptable registry, according to a statement issued in September 2004 (UMIN R000004736).

Participants

Major teaching hospitals within the metropolitan Tokyo area were selected for this study, and the study protocol was approved by the institutional review board committee at each site. Informed consent was waived because this was a database-oriented study. All consecutive PCI patients older than 18 years during the study period were registered, including failure cases.

Procedures and Data Collection

We analyzed data from 6,528 patients who had undergone PCI at any 1 of the 12 Japanese hospitals participating in the JCD between September 2008 and September 2013. Acute coronary syndrome (ACS) was defined as the patient presenting to the hospital with STEMI or NSTEMI/unstable angina (NSTE-ACS). We excluded patients who presented with preprocedural cardiopulmonary arrest or with preprocedural cardiogenic shock. Patients included in this study were divided into 2 groups based on preprocedural antiplatelet therapy: DAPT users and non-users.

Statistical Analysis and Study Endpoints

The study endpoints included in-hospital mortality, cardiogenic shock, HF, postprocedural MI (postprocedural creatine phosphokinase more than three times the upper limit), and bleeding complications. Bleeding complications in this registry were defined as those requiring transfusion, prolonging the hospital stay, and/or causing a decrease in hemoglobin level of >3.0 g/dl.

Continuous variables are expressed in terms of their means and standard deviations. Categorical variables are expressed as percentages. Continuous variables were compared by Student’s t-test, and differences between categorical variables were examined by χ² test. A multiple logistic regression analysis was performed to determine the independent predictors for in-hospital mortality, cardiogenic shock, HF, bleeding, and postprocedural MI. We performed covariate adjustment by using the propensity score; using this approach, the aforementioned outcome variables were regressed on an indicator variable denoting DAPT treatment status and the estimated propensity score. Factors included in the statistical model were the use/non-use of DAPT, age, female sex, previous MI, previous HF, diabetes mellitus, cerebrovascular disease, arteriosclerosis obliterans, chronic obstructive pulmonary disease, hypertension, smoking, juvenile coronary artery disease, history of coronary artery bypass grafting (CABG), chronic kidney disease stage ≥3, body mass index ≥30 kg/m², and propensity score for use of DAPT.

All statistical calculations and analyses were performed using SPSS version 20 (SPSS, Chicago, IL, USA), and P-values <0.05 were considered statistically significant.

Ethical Considerations

The JCD Steering Committee was responsible for overall study guidance, including the study protocol, data analyses, and interpretation of results. The Department of Healthcare Quality Assessment at Tokyo University independently managed the database. During the planning, implementation, and reporting of this study, there were no issues such as conflicts of interest, conflicts of responsibility, or intellectual property right concerns.

Results

A total of 6,528 consecutive patients who had undergone PCI during the study period were assessed. The average age of the patients was 67.4±11.4 years, and 1,366 patients (20.9%) were women. The number of patients with STEMI, NSTE-ACS, and stable angina was 1,924 (29.5%), 1,921 (29.4%), and 1,452 (22.2%), respectively. Of the 6,528 patients, 2,079 (31.8%) did not receive preprocedural DAPT. The majority of these non-DAPT patients received aspirin (89.6%), but the dispensing rates of second antiplatelet agents such as clopidogrel, ticlopidine, and cilostazol were low, with 59 (2.8%), 70 (3.4%), and 45 (2.2%) patients, respectively, receiving these agents.

Patient Population

The baseline clinical characteristics of the DAPT and non-DAPT groups are presented in Table 1. The numbers of patients who presented with hyperlipidemia, chronic kidney disease stage ≥3, prior HF, NSTEMI/unstable angina, and stable angina as indicators of PCI and radial artery puncture were significantly higher in the DAPT group than in the non-DAPT group. Prior HF, Canadian Cardiovascular Society (CCS) class 3/4 angina, STEMI as a PCI indicator, and femoral artery puncture were more common in the non-DAPT group.

Table 1. Baseline Clinical Characteristics of Each Group Based on Preprocedural Antiplatelet Therapy

	Non-DAPT (n=2,079), % (n)	DAPT (n=4,449), % (n)	P value
Age, years (median)	66.5±11.7	67.1±11.7	0.032
50–59	15.2 (315)	18.9 (842)	<0.001
60–69	28.3 (589)	33.7 (1,501)	<0.001
70–79	27.9 (581)	33.9 (1,510)	<0.001
>80	13.6 (282)	13.8 (614)	0.796
Female	24.5 (509)	19.3 (857)	<0.001
BMI	24.1±3.7	24.2±3.3	<0.001
Coronary risk factors
DM	37.2 (1,642)	37.7 (175)	0.840
DM with insulin	5.3 (111)	5.9 (264)	0.336
Hypertension	63.5 (1,320)	64.7 (2,877)	0.356
Hyperlipidemia	53.3 (1,108)	57.5 (2,557)	0.002
Smoking	35.2 (732)	34.5 (1,534)	0.564
Comorbidities
CVD	8.4 (175)	7.7 (343)	0.324
COPD	3.0 (62)	2.3 (101)	0.086
CKD stage ≥3	8.8 (182)	12.0 (535)	<0.001
PAD	6.0 (124)	6.0 (267)	0.953
History
Prior MI	6.6 (137)	6.7 (300)	0.871
Prior HF	6.5 (136)	5.0 (223)	0.012
Prior CABG	4.3 (89)	2.9 (127)	0.003
Presenting status
CCS class 3/4	24.1 (502)	20.7 (922)	0.002
CCS class 4	12.7 (265)	8.7 (388)	<0.001
HF	14.8 (308)	11.6 (517)	<0.001
NYHA class 3/4	8.3 (172)	6.9 (306)	0.044
Coronary status
2-vessel disease	33.6 (669)	43.1 (1,916)	<0.001
3-vessel disease	18.9 (392)	23.3 (1,037)	<0.001
LMT stenosis	6.7 (140)	8.4 (372)	0.023
PCI indication
STEMI <12 h	23.6 (491)	20.5 (913)	0.005
STEMI >12 h, unstable	5.8 (121)	5.3 (236)	0.393
NSTEMI/UA	31.6 (656)	28.4 (1,265)	0.045
Stable angina	18.2 (379)	24.1 (1,073)	<0.001
Puncture site
Radial artery	21.0 (437)	35.3 (1,569)	<0.001
Femoral artery	76.2 (1,584)	62.5 (4,449)	<0.001
Drug-eluting stent	52.1 (1,083)	63.0 (2,802)	<0.001
Bare metal stent	29.8 (619)	26.7 (1,186)	0.023
Single stent	41.5 (863)	56.5 (2,513)	<0.001
Multiple stents	40.4 (840)	33.2 (1,447)	<0.001
Single stent length (mm)	20.5±6.1	20.6±6.1	0.791
Multiple stent length (mm)	31.2±6.5	32.8±6.4	0.703

BMI, body mass index; CABG, coronary artery bypass grafting; CCS, Canadian Cardiovascular Society; CKD, chronic kidney disease; CVD, cerebrovascular disease; COPD, chronic obstructive pulmonary disease; DAPT, dual antiplatelet therapy; DM, diabetes mellitus; HF, heart failure; LMT, left main trunk; MI, myocardial infarction; NSTEMI, non-ST-elevation MI; PCI, percutaneous coronary intervention; PAD, peripheral artery disease; STEMI, ST-elevation MI; UA, unstable angina.

Propensity Score Analysis (Variables Associated With Non-Use of DAPT)

Table 2 shows the variables associated with non-use of preprocedural DAPT after adjustment: female sex (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.73–0.97, P<0.001), prior CABG (OR: 0.57, 95% CI: 0.43–0.77, P<0.001), CCS class 4 (OR: 0.71, 95% CI: 0.59–0.85, P<0.001), and HF on admission (OR: 0.60, 95% CI: 0.50–0.71, P<0.001) were all associated with DAPT non-use.

Table 2. Predictors of Use of DAPT

	OR	95% CI	P value
Age 60–69 years	1.57	1.37–1.80	<0.001
Age 70–79 years	1.58	1.37–1.82	<0.001
Age >80 years	1.54	1.27–1.86	<0.001
Female	0.84	0.73–0.97	0.017
BMI	1.12	1.02–1.22	0.013
Hypertension	1.25	1.10–1.42	<0.001
Hyperlipidemia	1.47	1.31–1.66	<0.001
Smoking	1.21	1.07–1.37	0.002
CKD stage ≥3	1.35	1.11–1.64	0.003
Without ischemic symptoms	1.34	1.12–1.62	0.002
Prior CABG	0.57	0.43–0.77	<0.001
CCS class 4	0.71	0.59–0.85	<0.001
HF	0.60	0.50–0.71	<0.001
Therapy for angina pectoris	1.22	1.03–1.44	0.022
Urgent PCI	1.17	1.04–1.33	0.011
3-vessel disease	1.25	1.09–1.45	0.002

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

In-Hospital Crude Outcomes

Table 3 shows the overall in-hospital outcomes and complications for the 2 groups. The combined rate of death, postprocedural shock, and HF was significantly higher in the non-DAPT group than in the DAPT group. Rates of hemodialysis introduction and postprocedural MI were also higher in the non-DAPT group than in the DAPT group. Notably, the rates of stent thrombosis and bleeding complications were similar in both groups.

Table 3. Outcomes According to Use of Preprocedural Antiplatelet Therapy

	Non-DAPT (n=2,079), % (n)	DAPT (n=4,449), % (n)	P value
Death, shock, HF	5.1 (105)	3.3 (146)	0.001
Death	1.3 (28)	1.1 (49)	0.392
Shock	2.3 (48)	1.6 (69)	0.032
HF	2.9 (61)	1.5 (67)	<0.001
Coronary dissection	1.3 (28)	1.1 (51)	0.490
Coronary perforation	0.9 (19)	1.0 (43)	0.838
Cerebral infarction	0.6 (13)	0.3 (15)	0.097
Cerebral bleeding	0.0 (1)	0.0 (1)	0.582
Cardiac tamponade	0.3 (7)	0.3 (14)	0.884
HD introduction	1.3 (27)	0.4 (19)	<0.001
Thrombosis	0.0 (0)	0.1 (6)	0.094
Blood transfusion	1.9 (39)	1.6 (73)	0.496
Bleeding <72 h
Puncture site	0.8 (16)	0.9 (38)	0.725
Hematoma	0.8 (17)	1.0 (45)	0.452
Retroperitoneal hemorrhage	0.0 (1)	0.0 (2)	0.956
Gastrointestinal bleeding	0.4 (9)	0.2 (11)	0.206
Urological bleeding	0.1 (2)	0.1 (5)	0.852
Other bleeding	0.9 (18)	0.7 (31)	0.461
Postprocedural MI	38.1 (622)	28.7 (1,167)	<0.001

HD, hemodialysis. Other abbreviations as in Table 1.

In-Hospital Adjusted Outcomes

Multivariate logistic regression analysis showed that DAPT use was 1 of the independent predictors for improved combined outcomes of death, postprocedural shock, and HF (OR: 0.68, 95% CI: 0.51–0.91, P=0.009), and for postprocedural MI (OR: 0.71, 95% CI: 0.59–0.85, P<0.001). Receiving preprocedural DAPT showed noninferiority in bleeding complications (OR: 1.02, 95% CI: 0.63–1.40, P=0.764) (Figure A).

Figure.

(A) Adjusted in-hospital outcomes. Forest plot of odds ratios (ORs) and 95% confidence intervals (CIs) for in-hospital outcomes among patients who did or did not undergo dual antiplatelet therapy (DAPT) before percutaneous coronary intervention (PCI). (B) Adjusted in-hospital outcomes in ST-elevation MI (STEMI) patients. Forest plot of ORs and 95% CIs for in-hospital outcomes among STEMI patients who did or did not undergo DAPT before PCI. (C) Adjusted in-hospital outcomes in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. Forest plot of ORs and 95% CIs for in-hospital outcomes among NSTE-ACS patients who did or did not undergo DAPT before PCI. HF, heart failure; MI, myocardial infarction.

Subgroup analyses of STEMI and NSTE-ACS were performed (Tables 4–7). In the STEMI subgroup, DAPT use was associated with reduced risk of postprocedural MI (OR: 0.74, 95% CI: 0.57–0.96, P=0.026). There was also a trend toward a lower risk for combined outcomes of death, postprocedural shock, and HF (OR: 0.73, 95% CI: 0.51–1.04, P=0.079). In the NSTE-ACS subgroup, DAPT use was associated with reduced risk of postprocedural MI (OR: 0.69, 95% CI: 0.52–0.92, P=0.012). No additional risk of bleeding complications was noted in either the STEMI (OR: 0.89, 95% CI: 0.49–1.63, P=0.710) or the NSTE-ACS (OR: 1.02, 95% CI: 0.51–2.03, P=0.952) subgroup (Figures B,C).

Table 4. Baseline Clinical Characteristics of STEMI Patients in Each Group According to Use of Preprocedural Antiplatelet Therapy

	Non-DAPT (n=650), % (n)	DAPT (n=1,274), % (n)	P value
Age, years (median)	66.8±12.4	65.1±12.4	0.006
50–59	20.8 (135)	22.6 (288)	0.358
60–69	31.4 (204)	33.2 (423)	0.421
70–79	28.2 (183)	26.3 (335)	0.385
>80	15.5 (101)	13.3 (169)	0.175
Female	22.6 (147)	19.8 (252)	0.147
BMI	24.1±3.7	23.6±3.7	0.972
Coronary risk factors
DM	32.0 (208)	31.6 (403)	0.870
DM with insulin	3.7 (24)	4.4 (56)	0.465
Hypertension	62.3 (405)	61.8 (787)	0.820
Hyperlipidemia	51.8 (337)	57.1 (727)	0.029
Smoking	45.7 (297)	45.4 (578)	0.893
Comorbidities
CVD	6.6 (43)	7.2 (92)	0.623
COPD	2.9 (19)	1.9 (24)	0.145
CKD stage ≥3	10.8 (70)	10.1 (129)	0.661
PAD	2.8 (18)	3.4 (43)	0.473
History
Prior MI	3.2 (21)	3.2 (41)	0.988
Prior HF	3.8 (25)	2.1 (27)	0.027
Prior CABG	1.2 (8)	0.9 (11)	0.441
Presenting status
HF	17.1 (111)	11.1 (141)	<0.001
NYHA class 3/4	10.3 (67)	7.1 (91)	0.017
Coronary status
2-vessel disease	33.7 (219)	38.5 (490)	0.040
3-vessel disease	20.3 (132)	22.6 (288)	0.248
LMT stenosis	5.1 (33)	6.0 (77)	0.388
PCI indication
STEMI <12 h	73.8 (480)	70.4 (897)	0.114
STEMI >12 h, unstable	18.2 (118)	18.1 (230)	0.957
Puncture site
Radial artery	7.1 (46)	21.6 (275)	<0.001
Femoral artery	91.5 (595)	77.7 (990)	<0.001
Door to balloon time (min)	104.9±62.8	98.0±57.6	0.044

Abbreviations as in Table 1.

Table 5. Outcomes of STEMI Patients in Each Group According to Use of Preprocedural Antiplatelet Therapy

	Non-DAPT (n=656), % (n)	DAPT (n=1,265), % (n)	P value
Death, shock, HF	10.9 (71)	6.9 (88)	0.002
Death	2.8 (18)	2.6 (33)	0.817
Shock	3.8 (25)	3.2 (41)	0.474
HF	7.1 (46)	3.5 (44)	<0.001
Coronary dissection	1.8 (12)	1.0 (13)	0.130
Coronary perforation	1.1 (7)	0.8 (10)	0.517
Cerebral infarction	0.9 (6)	0.6 (7)	0.344
Cerebral bleeding	0.2 (1)	0.1 (1)	0.628
Cardiac tamponade	0.8 (5)	0.7 (9)	0.878
HD introduction	2.0 (13)	0.3 (4)	<0.001
Thrombosis	0.0 (0)	0.2 (3)	0.216
Blood transfusion	2.5 (16)	2.2 (28)	0.714
Bleeding <72 h
Puncture site	0.6 (4)	0.9 (11)	0.558
Hematoma	0.8 (5)	0.7 (9)	0.878
Retroperitoneal hemorrhage	0.2 (1)	0.0 (0)	0.161
Gastrointestinal bleeding	0.8 (5)	0.4 (5)	0.277
Urological bleeding	0.2 (1)	0.2 (3)	0.710
Other bleeding	1.2 (8)	1.3 (16)	0.963
Postprocedural MI	80.5 (503)	75.3 (940)	0.012

Abbreviations as in Tables 1,3.

Table 6. Baseline Clinical Characteristics of NSTE-ACS Patients in Each Group According to Use of Preprocedural Antiplatelet Therapy

	Non-DAPT (n=656), % (n)	DAPT (n=1,265), % (n)	P value
Age, years (median)	68.8±11.5	67.9±11.5	0.127
50–59	13.4 (88)	18.2 (230)	0.008
60–69	26.2 (172)	31.5 (399)	0.016
70–79	24.8 (163)	34.8 (440)	<0.001
>80	15.4 (101)	15.9 (201)	0.778
Female	26.2 (172)	21.5 (272)	0.020
BMI	23.9±3.6	24.2±3.7	0.088
Coronary risk factors
DM	31.6 (207)	33.0 (417)	0.532
DM with insulin	5.2 (34)	5.0 (63)	0.847
Hypertension	67.5 (443)	66.5 (841)	0.644
Hyperlipidemia	55.6 (365)	58.7 (743)	0.193
Smoking	34.6 (277)	35.8 (453)	0.600
Comorbidities
CVD	10.7 (70)	7.4 (93)	0.013
COPD	3.7 (24)	2.5 (31)	0.132
CKD stage ≥3	9.0 (59)	14.3 (181)	0.001
PAD	5.3 (25)	4.3 (54)	0.292
History
Prior MI	5.5 (36)	5.1 (64)	0.688
Prior HF	5.8 (38)	5.4 (68)	0.704
Prior CABG	4.3 (28)	2.3 (29)	0.016
Presenting status
CCS class 3/4	51.5 (338)	52.5 (664)	0.688
CCS class 4	30.5 (200)	25.6 (324)	0.023
HF	14.0 (92)	14.4 (182)	0.829
NYHA class 3/4	9.0 (59)	10.0 (126)	0.496
Coronary status
2-vessel disease	34.8 (228)	45.6 (577)	<0.001
3-vessel disease	18.1 (119)	23.8 (301)	0.004
LMT stenosis	7.5 (49)	9.0 (114)	0.250
PCI indication
NSTEMI	30.3 (199)	33.8 (427)	0.129
UA	69.7 (457)	66.2 (838)	0.129
Puncture site
Radial artery	24.2 (159)	39.4 (499)	<0.001
Femoral artery	73.0 (479)	58.8 (740)	<0.001

ACS, acute coronary syndrome. Other abbreviations as in Table 1.

Table 7. Outcomes of NSTE-ACS Patients in Each Group According to Use of Preprocedural Antiplatelet Therapy

	Non-DAPT (n=656), % (n)	DAPT (n=1,265), % (n)	P value
Death, shock, HF	3.5 (23)	2.5 (32)	0.224
Death	1.4 (9)	0.8 (10)	0.222
Shock	2.3 (15)	0.9 (12)	0.018
HF	1.7 (11)	1.1 (14)	0.296
Coronary dissection	0.9 (6)	0.9 (12)	0.942
Coronary perforation	0.6 (4)	0.7 (9)	0.797
Cerebral infarction	0.9 (6)	0.6 (7)	0.360
Cerebral bleeding	0.0 (0)	0.0 (0)
Cardiac tamponade	0.2 (1)	0.2 (2)	0.976
HD introduction	2.0 (13)	0.9 (12)	0.058
Thrombosis	0.0 (0)	0.2 (3)	0.212
Blood transfusion	2.7 (18)	1.4 (18)	0.043
Bleeding <72 h
Puncture site	0.6 (4)	0.9 (11)	0.540
Hematoma	0.9 (6)	1.1 (14)	0.694
Retroperitoneal hemorrhage	0.0 (0)	0.1 (1)	0.471
Gastrointestinal bleeding	0.6 (4)	0.3 (4)	0.343
Urological bleeding	0.2 (1)	0.2 (2)	0.976
Other bleeding	1.1 (7)	0.6 (8)	0.305
Postprocedural MI	18.6 (98)	15.2 (178)	0.083

Abbreviations as in Tables 1,3,6.

Discussion

Approximately one-third of Japanese patients do not receive preprocedural DAPT before undergoing PCI despite the strong recommendations from clinical guidelines. The rate of preprocedural DAPT use in the present study was consistent with previously reported registry data,¹³ suggesting that our data were representative of a real-world situation. In our propensity-adjusted analysis of the multicenter registry data, DAPT use before undergoing PCI was associated with reduced risk of postprocedural MI. DAPT use showed a clinically noticeable, although not significant, trend toward reduced risk of combined outcomes of death, postprocedural cardiogenic shock, and HF. This was consistent across all subgroups, including patients with STEMI and NSTE-ACS.

Although DAPT is frequently used to reduce acute thrombotic events in modern PCI management, its efficacy in Japanese patients, who are susceptible to bleeding complications, remains controversial. Previous studies of patients with ACS, particularly those who have undergone PCI, have shown that preprocedural DAPT has beneficial effects, possibly by reducing subacute stent thrombosis, periprocedural ischemia, and distal embolization. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,³ early administration of clopidogrel decreased the number of Q-wave MI and significantly improved in-hospital and 1-year outcomes. The Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA-2) study²¹ showed that 600 mg clopidogrel administered preprocedurally significantly reduced periprocedural MI compared with 300 mg clopidogrel, possibly by greater and faster platelet inhibition. After publication of those studies and inclusion as well as implementation in the guidelines, pretreatment with 300 mg clopidogrel before PCI has been widely used in PCI management in Japan. The present study confirmed that DAPT non-users have a greater degree of postprocedural myocardial damage. The effect of periprocedural MI on the long-term prognosis for patients undergoing PCI has been controversial;^22–26 however, the occurrence of periprocedural MI above a certain threshold seems to be associated with a higher risk of late mortality.

Because previous studies have shown a significant association between guideline-based care processes and in-hospital mortality,²⁷ further efforts to implement the appropriate clinical use of DAPT are necessary. Nevertheless, issues do arise that lead to omission of DAPT, such as the patient’s inability to take oral medication, true contraindications such as allergy and active bleeding, or the primary medical staff not recognizing the importance of preprocedural DAPT. These omissions may have different clinical impacts. In addition, our study indicated that prior CABG, CCS class 4, and HF on admission were independent predictors of preprocedural DAPT non-use. Patients with significant angina, such as those with CCS class 4, may be rushed to the catheter laboratory with inadequate time for DAPT administration, and it may be difficult for patients with HF to take oral medication. Recognizing these clinical scenarios as potential causes of DAPT non-use could aid in improving the implementation of appropriate care and patient outcomes by developing solutions for such situations. Our data also showed differences in the rate of DAPT use among hospitals (Figure S1).

The incidence of procedure-related bleeding associated with DAPT use has varied in previous studies. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²⁸ for primary prevention and the CURE trial³ for secondary prevention of NSTE-ACS showed an increased risk of long-term bleeding in DAPT users. In contrast, PCI-related trials, such as PCI-CURE,²⁹ PCI-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY),² Clopidogrel for the Reduction of Events During Observation (CREDO),¹ and ARMYDA-2,²¹ showed that DAPT did not increase the risk of short-term bleeding complications. Our study results agreed with these findings. We also noted that the incidence of bleeding events was similar to that of the J-AMI registry¹³ This is of particular importance, because East Asians, including Japanese, are known to be vulnerable to bleeding during invasive procedures. Previous studies have shown that Asian patients with NSTE-ACS have a significantly higher bleeding risk than non-Asian Caucasians (13.4% vs. 9.4%, P<0.0001),¹¹ indicating ethnic variability in antithrombotic susceptibility.³⁰ A lower loading dose of clopidogrel (300 mg) and/or frequent use of radial artery access might have contributed to lowering the risk of bleeding in our dataset.

Study Limitations

First, because this study was an analysis of a multicenter cohort study rather than an observational and nonrandomized trial, unmeasured and unaccounted variables may have confounded the observed associations. Second, the study population was limited. Despite a large number of procedures performed in Japan (>200,000 annually), the number of procedures performed in each hospital was limited. Third, specific reasons for DAPT non-use were not available in the JCD Keio interhospital Cardiology Study database. The condition of patients in the non-DAPT group may have been more critical than that of patients in the DAPT group, which could have biased the results. For example, intravascular ultrasound imaging was used more frequently in the non-DAPT group (40.2% vs. 20.2%; P<0.001, respectively for non-DAPT and DAPT groups). Because the overall procedure-related complications were similar (2.2% vs. 2.1%; P=0.49), the inadequate use of intravascular imaging is probably not the sole reason for increased events, but does represent the complexity of this issue. Fourth, warfarin intake data were not available in the database, and could affect both the decision to forgo DAPT and the bleeding rate. The use of warfarin at discharge was noted to be higher in the non-DAPT compared with the DAPT group (7.7% vs. 9.9%; P<0.001), albeit a relatively low rate of warfarin use in both groups likely precludes a major effect of anticoagulation therapy in our analysis. Fifth, neither genetic phenotype information nor the quantitative information of thienopyridine resistance was available in our dataset. However, according to our present data (and also consistent with the result from J-AMI registry), the rate of stent thrombosis was substantially lower than that of non-Asians. Sixth, the exact timing of DAPT administration before PCI was unavailable in the database. Finally, we did not evaluate the effect of preprocedural DPAT on long-term clinical outcomes among patients who had undergone PCI. This should be a future consideration.

Conclusions

A significant number of Japanese PCI patients do not receive preprocedural DAPT; however, in our study, PCI patients who underwent DAPT had a lower combined risk of death, postprocedural shock, HF, and a lower risk of postprocedural MI without any obvious risk of bleeding. Thus, preprocedural DAPT seems to be beneficial across patient populations, and further effort is needed to implement the use of DAPT in real-world PCI.

Acknowledgments

This research was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (KAKENHI No. 25460630 [S.K.] and 25460777 [I.U.]) and by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.

Conflicts of Interest

None.

Contributors

Y.I., S.K., and I.U. conceived and designed the research, and drafted the manuscript. Y.I., S.K., and H.M. analyzed and interpreted the data. H.M. performed the statistical analysis. S.K. and K.F. handled funding and supervision; J.F., M.S., Y.S., Y.N., K.N., I.N., Y. Maekawa, Y. Momiyama, K.F. made critical revisions of the manuscript for important intellectual content.

Supplementary Files

Supplementary File 1

Figure S1. Use of dual antiplatelet therapy (DAPT) in each institute participating in study of use of preprocedural antiplatelet therapy in Japanese patients undergoing percutaneous coronary intervention.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-15-0484

References

• 1.    Steinhubl  SR,  Berger  PB,  Mann  JT 3rd,  Fry  ET,  DeLago  A,  Wilmer  C, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 2002; 288: 2411–2420.
• 2.    Sabatine  MS,  Cannon  CP,  Gibson  CM,  Lopez-Sendon  JL,  Montalescot  G,  Theroux  P, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: The PCI-CLARITY study. JAMA 2005; 294: 1224–1232.
• 3.    Yusuf  S,  Zhao  F,  Mehta  SR,  Chrolavicius  S,  Tognoni  G,  Fox  KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494–502.
• 4.    O’Gara  PT,  Kushner  FG,  Ascheim  DD,  Casey  DE Jr,  Chung  MK,  de Lemos  JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: e78–e140, doi:10.1016/j.jacc.2012.11.019.
• 5.    Levine  GN,  Bates  ER,  Blankenship  JC,  Bailey  SR,  Bittl  JA,  Cercek  B, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011; 124: e574–e651, doi:10.1161/CIR.0b013e31823ba622.
• 6.    Windecker  S,  Kolh  P,  Alfonso  F,  Collet  JP,  Cremer  J,  Falk  V, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). EuroIntervention 2015; 10: 1024–1094.
• 7.   Japanese Circulation Society guidelines for the management of patients with ST-elevation myocardial infarction 2008 [in Japanese].
• 8.   Japanese Circulation Society guidelins for the management of patients without persistent ST segment elevation 2007 [in Japanese].
• 9.    Amsterdam  EA,  Wenger  NK,  Brindis  RG,  Casey  DE,  Ganiats  TG,  Holmes  DR, et al. 2014 AHA/ACC Guideline for the management of patients with non-ST-elevation acute coronary syndromes. Journal of the American College of Cardiology 2014; 64: e139–e228, doi:10.1016/j.jacc.2014.09.017.
• 10.   JCS Joint Working Group. Guidelines for elective percutaneous coronary intervention in patients with stable coronary artery disease (JCS 2011) published in 2012: Digest version. Circ J 2013; 77: 1590–1607.
• 11.    Wang  TY,  Chen  AY,  Roe  MT,  Alexander  KP,  Newby  LK,  Smith  SC Jr, et al. Comparison of baseline characteristics, treatment patterns, and in-hospital outcomes of Asian versus non-Asian white Americans with non-ST-segment elevation acute coronary syndromes from the CRUSADE quality improvement initiative. Am J Cardiol 2007; 100: 391–396.
• 12.    Kawaji  T,  Shiomi  H,  Morimoto  T,  Tamura  T,  Nishikawa  R,  Yano  M, et al. Long-term efficacy and safety outcomes after unrestricted use of drug-eluting stents in patients with acute coronary syndrome. Circ J 2014; 78: 1628–1635.
• 13.    Nakamura  M,  Yamagishi  M,  Ueno  T,  Hara  K,  Ishiwata  S,  Itoh  T, et al. Current Antiplatelet therapy for Japanese patients with ST elevation acute myocardial infarction: J-AMI registry. Cardiovasc Interv Ther 2013; 28: 162–169.
• 14.    Mogi  S,  Kohsaka  S,  Miyata  H,  Kawamura  A,  Noma  S,  Suzuki  M, et al. Comparison between working day and holiday acute coronary syndrome presentation. Int J Cardiol 2011; 153: 85–87.
• 15.    Ohno  Y,  Maekawa  Y,  Miyata  H,  Inoue  S,  Ishikawa  S,  Sueyoshi  K, et al. Impact of periprocedural bleeding on incidence of contrast-induced acute kidney injury in patients treated with percutaneous coronary intervention. J Am Coll Cardiol 2013; 62: 1260–1266.
• 16.    Kodaira  M,  Kawamura  A,  Miyata  H,  Noma  S,  Suzuki  M,  Ishikawa  S, et al. Door to balloon time: How short is enough under highly accessible nationwide insurance coverage? Analysis from the Japanese multicenter registry. Int J Cardiol 2013; 168: 534–536.
• 17.    Numasawa  Y,  Kohsaka  S,  Miyata  H,  Kawamura  A,  Noma  S,  Suzuki  M, et al. Safety of transradial approach for percutaneous coronary intervention in relation to body mass index: A report from a Japanese multicenter registry. Cardiovasc Interv Ther 2013; 28: 148–156.
• 18.    Messenger  JC,  Ho  KK,  Young  CH,  Slattery  LE,  Draoui  JC,  Curtis  JP, et al. The National Cardiovascular Data Registry (NCDR) data quality brief: The NCDR data quality program in 2012. J Am Coll Cardiol 2012; 60: 1484–1488.
• 19.    Ogawa  H,  Hokimoto  S,  Kaikita  K,  Yamamoto  K,  Chitose  T,  Ono  T, et al. Current status and prospects of antiplatelet therapy in percutaneous coronary intervention in Japan: Focus on adenosine diphosphate receptor inhibitors. J Cardiol 2011; 58: 6–17.
• 20.    Nakagawa  Y,  Nobuyoshi  M,  Yamaguchi  T,  Meguro  T,  Yokoi  H,  Kimura  T, et al. Efficacy of abciximab for patients undergoing balloon angioplasty: Data from Japanese evaluation of c7E3 Fab for elective and primary PCI organization in randomized trial (JEPPORT). Circ J 2009; 73: 145–151.
• 21.    Patti  G,  Colonna  G,  Pasceri  V,  Pepe  LL,  Montinaro  A,  Di Sciascio  G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005; 111: 2099–2106.
• 22.    Prasad  A,  Gersh  BJ,  Bertrand  ME,  Lincoff  AM,  Moses  JW,  Ohman  EM, et al. Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: An analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009; 54: 477–486.
• 23.    Damman  P,  Wallentin  L,  Fox  KA,  Windhausen  F,  Hirsch  A,  Clayton  T, et al. Long-term cardiovascular mortality after procedure-related or spontaneous myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome: A collaborative analysis of individual patient data from the FRISC II, ICTUS, and RITA-3 trials (FIR). Circulation 2012; 125: 568–576.
• 24.    Jang  JS,  Jin  HY,  Seo  JS,  Yang  TH,  Kim  DK,  Kim  DS, et al. Prognostic value of creatine kinase-myocardial band isoenzyme elevation following percutaneous coronary intervention: A meta-analysis. Catheter Cardiovasc Interv 2013; 81: 959–967.
• 25.    Zimarino  M,  Affinito  V. The prognosis of periprocedural myocardial infarction after percutaneous coronary interventions. Cardiovasc Revasc Med 2013; 14: 32–36.
• 26.    Gili  S,  D’Ascenzo  F,  Moretti  C,  Omede  P,  Vilardi  I,  Bertaina  M, et al. Impact on prognosis of periprocedural myocardial infarction after percutaneous coronary intervention. J Interv Cardiol 2014; 27: 482–490.
• 27.    Peterson  ED,  Roe  MT,  Mulgund  J,  DeLong  ER,  Lytle  BL,  Brindis  RG, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA 2006; 295: 1912–1920.
• 28.    Bhatt  DL,  Topol  EJ. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: Rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J 2004; 148: 263–268.
• 29.    Mehta  SR,  Yusuf  S,  Peters  RJ,  Bertrand  ME,  Lewis  BS,  Natarajan  MK, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001; 358: 527–533.
• 30.    Nakata  T,  Miyahara  M,  Nakatani  K,  Wada  H,  Tanigawa  T,  Komada  F, et al. Relationship between CYP2C19 loss-of-function polymorphism and platelet reactivities with clopidogrel treatment in Japanese patients undergoing coronary stent implantation. Circ J 2013; 77: 1436–1444.